Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue

Abstract

A number of analogues of the marine-derived histone deacetylase inhibitor largazole incorporating major structural changes in the depsipeptide ring were synthesized. Replacing the thiazole-thiazoline fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity profile similar to that of largazole, suggesting that conformational change accompanying switching hybridization from sp3 to sp2at C-7 is well tolerated. Analogue 7 was more class I selective compared to largazole, with at least 464-fold selectivity for class I HDAC proteins over class II HDAC6 compared to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic largazole analogue not containing a thiazoline ring. The elimination of a chiral center derived from the unnatural amino acid R-α-methylcysteine makes the molecule more amenable to chemical synthesis and, coupled with its increased class I selectivity, 7 could serve as a new lead compound for developing selective largazole analogues.

Largazole Analogues as Histone Deacetylase Inhibitors and Anticancer Agents: An Overview of Structure–Activity Relationships

“…In contrast, the pyridyl analogue 40 was unexpectedly not able to block tumorp roliferation, maybeb ecause of poor pharmacokinetic properties or high plasma protein binding, although further experiment pointed out that ab etter efficacy might be obtained with more frequent or higherdosing. [37] Very recently,aseries of new largazole analogues structurally relatedt oc ompound 37 were reported by Tillekeratne and coworkers, [38] which synthesized analogues with ap yridine ring in place of the thiazole group ( Figure 10). Among these,c ompound 41 presented an endocyclic amine substituted with a methyl group in place of the thiazoline moiety,w hile compounds 42 and 43 were, respectively characterizedb yt he presence of ap olyether group and ab ipyridine fragment replacing the thiazole-thiazoline moiety of largazole.…”

“…Very recently, a series of new largazole analogues structurally related to compound 37 were reported by Tillekeratne and co‐workers, which synthesized analogues with a pyridine ring in place of the thiazole group (Figure ). Among these, compound 41 presented an endocyclic amine substituted with a methyl group in place of the thiazoline moiety, while compounds 42 and 43 were, respectively characterized by the presence of a polyether group and a bipyridine fragment replacing the thiazole‐thiazoline moiety of largazole.…”

Impact of Cross-Coupling Reactions in Drug Discovery and Development

“…Using natural products as starting points, medicinal chemists have modified the core structure of the cyclopeptide to increase pharmacological activity and drug-like properties. There are examples of introducing biaryl systems within the cyclopeptide core like largazole [59] derivatives resulting in higher selectivity and potency. Recently Sewald [60] and colleagues developed a new methodology applying Suzuki−Miyaura cross-coupling reactions (in solution or on-resin) to introduce a biaryl moiety into an Arg-Gly-Asp (also known as RGD) cyclopeptide providing new SAR direction.…”

Thiazole Moiety: An Interesting Scaffold for Developing New Antitumoral Compounds

“…Substitution of thiazole by pyridyl residues and depsipeptide framework alteration to peptide isostere led to equipotent largazole analogues but with improved selectivity for different HDACs [86]. The replacement of thiazole and thiazoline by bipyridyl fragments led to derivatives with a similar activity of largazole, but with an improved selectivity for class I HDAC [87].…”